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On incubation with the postmitochondrial fraction of the liver homogenate of rabbits, guinea-pigs, rats, and mice in the presence of NADPH and oxygen, the alpha-sympathomimetic trans-3-(2-hydroxyethylamino)-5,8-dimethoxy-1,2,3,4-tetrahydro-2-n aphthol (Tetraminol, 1) is preferentially O-demethylated in position 8, yielding metabolite 3. In male rats O-demethylation is stronger than in females.
In this commentary, the indirect sympathomimetic effect of tyramine and the phenomenon of tyramine tachyphylaxis are reinterpreted in terms of carrier-mediated exchange processes. Extracellular tyramine would exchange with intraterminal noradrenaline and, upon repeated tyramine administration, with a mixture of noradrenaline and tyramine progressively more enriched in the pharmacologically inactive amine.
A study comparing the chronic effects of propranolol (n = 21) and pindolol (n = 19) on male patients with stable angina pectoris was performed. Left ventricular function was assessed by serial radionuclide ventriculography. Radionuclide ventriculography was performed at rest and during cold pressor test. Both drugs improved symptoms of angina pectoris by at least one division of the New York Heart Association classification. Cold pressor testing caused increases in heart rate and blood pressure in both groups throughout the study. At rest, pretreatment ejection fraction was similar in both groups. During propranolol treatment this rose sequentially from 49% to 55% at 26 weeks. No change in the resting ejection fraction occurred in those taking pindolol. The difference in response between the groups reached significance at 26 weeks. In those with subnormal left ventricular ejection fraction (less than 50%), resting ejection fraction improved significantly throughout treatment with propranolol rising from a basal value of 39% to 51% at 26 weeks. In comparison, pindolol caused no significant change. There is no apparent advantage to intrinsic sympathomimetic activity in terms of preservation or improvement of left ventricular performance in patients with stable angina pectoris prescribed beta-blockers for extended periods of time.
Pretreatment with the selective noradrenergic uptake inhibitors nisoxetine and desipramine antagonized the locomotor stimulant effect of d-amphetamine without reducing the drug's stereotypy-inducing action. A similar antagonism was observed with imipramine but not with fluoxetine, a selective serotonin uptake inhibitor and structural analog of nisoxetine. The order of potency of antagonism was desipramine greater than nisoxetine greater than imipramine. Nisoxetine also selectively reduced the locomotor activity induced by maximally effective doses of cocaine, d-N-ethyl-amphetamine, and methylphenidate, but not that induced by morphine. Biochemically, nisoxetine blocked the selective reduction in cerebral cortical endogenous and 3H-norepinephrine produced by amphetamine with itself significantly altering either measure. These data support the involvement of norepinephrine in the locomotor stimulant action of indirectly acting sympathomimetic amines.
The relevance of the intrinsic sympathomimetic activity (ISA) of beta-blocking compounds to the clinical therapeutics of acute myocardial infarction was evaluated in 20 patients with an uncomplicated acute myocardial infarction by comparing the haemodynamic effects of equivalent beta-blocking doses of propranolol (non-cardioselective; no ISA) and pindolol (non-cardioselective; 50% ISA). Consecutive eligible male patients admitted to a Coronary Care Unit were randomised following a 1 h control period to two separate studies. In Study 1 the short-term dose-response effects of propranolol (1-8 mg) or pindolol (0.1-0.8 mg) were assessed. In Study 2 comparison of the effects of single i.v. propranolol (8 mg) and pindolol (0.8 mg) doses was undertaken over 6 h. Haemodynamic variables and thermodilution cardiac output were subsequently recorded to compare the effects of each drug on the circulation. The plasma concentrations of propranolol and pindolol were in the recognised therapeutic range. Both drugs were clinically well-tolerated, the changes induced in haemodynamic variables following each drug demonstrated effective beta-blockade. Within the limits of the experimental protocol, these data did not suggest definite haemodynamic advantage for ISA of pindolol in acute myocardial infarction. These findings are perhaps due to sympathetic activation in acute myocardial infarction attenuating the haemodynamic impact of ISA.
Six healthy volunteers took part in a randomized, single-blind, crossover study to quantitate the intrinsic sympathomimetic activity (ISA) of penbutolol in comparison with one drug possessing ISA (alprenolol) and with the standard non-ISA drug (propranolol). Single intravenous and one week oral administrations were studied. Complete parasympathetic and sympathetic isolation of the heart was obtained by administration of atropine 0.04 mg/kg body weight i.v. and propranolol 0.4 mg/kg i.v., or corresponding equipotent doses of alprenolol 0.4 mg/kg i.v. and penbutolol i.v. 0.08 mg/kg. In the chronic, oral study propranolol 160 mg b.i.d. was given, or corresponding equipotent doses of alprenolol (400 mg b.i.d.) or penbutolol (40 mg b.i.d.). The test procedure included measurement of heart rate and blood pressure in the supine, sitting and standing positions, and during isometric and dynamic exercise. ISA was calculated by comparison of the change in of heart rate with that produced by propranolol. The ISA of alprenolol was 22--26% and of penbutolol 12--18% of maximal sympathetic activity. Isometric and dynamic exercise gave comparable ISA values.
The pharmacological methods used to assess the intrinsic sympathomimetic activity (ISA) of beta-blockers are discussed. The clinical relevance of ISA to respiratory function, peripheral resistance and cardiac function is reviewed. It appears doubtful whether ISA is always of predominant clinical significance and an alternative explanation is offered for many clinical effects observed with certain beta-blockers, e.g. pindolol, oxprenolol, tolamolol, metoprolol, etc. Some effects of these beta-blockers resemble those of labetalol, a new drug with both alpha and beta-blocking activity. Some clinical effects of certain beta-blockers are more likely to be due to alpha-blocking activity than to their ISA.
Abrupt withdrawal of beta-adrenoceptor antagonists may lead to "rebound-effects". To study the mechanism underlying this phenomenon, the effects of the nonselective beta-adrenoceptor antagonists propranolol [no intrinsic sympathomimetic activity (ISA)], alprenolol (weak ISA) and mepindolol (strong ISA) on lymphocyte beta 2-adrenoceptor density--assessed by (+/-)-[125I]-iodocyanopindolol (ICYP) binding--and plasma renin activity (PRA) were investigated in male healthy volunteers aged 23-35 years. Propranolol treatment (4 X 40 mg/day) increased the density of beta 2-adrenoceptors by 25% after 2 days; concomitantly PRA and heart rate were reduced. During treatment beta 2-adrenoceptor density remained elevated. After withdrawal of propranolol PRA reached pre-drug levels rapidly, while heart rate was significantly enhanced. Beta 2-Adrenoceptor density, however, declined slowly being still significantly increased after 3 days, although propranolol was not detectable in plasma after 24 h. The affinity of ICYP to beta 2-adrenoceptors was not changed during or after treatment. Mepindolol treatment (2 X 5 mg/day) caused a 30% decrease of beta 2-adrenoceptor density and PRA after 2 days; both parameters remained reduced during treatment. After withdrawal, PRA reached rapidly pre-drug levels, whereas beta 2-adrenoceptor density was still after 4 days significantly diminished. The KD-values for ICYP, however, were not changed. During and after treatment heart rate was not affected. Alprenolol treatment (4 X 100 mg/day) led to a rapid fall in PRA, but did not significantly affect beta 2-adrenoceptor density. It is concluded, that the ISA may play an important role in modulating beta 2-adrenoceptor density and hence tissue responsiveness to beta-adrenoceptor stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)
We have studied the effect of isometheptene, an indirectly acting sympathomimetic with analgesic and antispastic properties, on secretin-cholecystokinin-stimulated pancreatic and biliary outputs. Isometheptene, infused intravenously at a dose of 100 mg in 30 min, significantly inhibited bicarbonate, enzyme, and bilirubin output in eight healthy subjects (compared to control values, the maximum percent inhibition was 34% for bicarbonate, 57% for lipase, 61% for chymotrypsin, and 86% for bilirubin). In four cholecystectomized subjects, the drug inhibited only pancreatic outputs. The inhibitory effect on pancreatic secretion, coupled with the analgesic action, suggest a potential benefit of this drug in acute pancreatic pathology.
The purpose of this study was to investigate the potential of beta-phenylethylamine (PEA), an amphetamine-like compound present in the blood during high stress situations, to protect rat gastric mucosa against absolute ethanol. F-344 rats were pretreated with PEA in saline at several dose levels and at various times prior to oral administration of 1 ml absolute ethanol. PEA at dose levels of 50 and 100 mg/kg significantly reduced the severity of alcohol-induced lesions following oral, but not parenteral, treatment. The duration of protection with PEA was approximately 90 min, with maximum protection observed when PEA was administered 15-30 min before alcohol. Pretreatment with indomethacin did not prevent or reduce the protection induced by PEA. Other sympathomimetic amines such as isoproterenol and ephedrin were similarly cytoprotective against absolute ethanol while amphetamine, phenylephrine, and epinephrine proved ineffective. These results add further support to the role of the sympathetic nervous system in regulating gastric mucosal protection in the rat.
In anaesthetized, artificially respirated mongrel dogs, the intravenous infusion of oxprenolol (0.3 mg and 1 mg/kg over 10 minutes) led to an increase in heart rate and cardiac output. Blood pressure in the pulmonary capillaries and right atrium, and vascular resistance were reduced. The pressure in the aorta was transiently decreased. Infusion of propranolol in the same doses was followed by a decrease in heart rate and cardiac output. The calculated peripheral resistances, pulmonary capillary pressure and right-atrial pressure increased slightly. Pressure in the aorta diminished slightly. In the light of the present results, it is evident that the intrinsic sympathomimetic activity of oxprenolol has a significant bearing on its haemodynamic effects in the anaesthetized dog.
Experiments on frog neuromuscular junction preparations with extracellular recording of nerve terminal action potentials and single-quantum end-plate currents (EPC) were used to assess the time course of evoked quantum secretion of mediator by analyzing histograms of the distribution of true synaptic delays. These studies showed that noradrenaline, isoproterenol, and dobutamine change the kinetics of secretion of quanta, leading to synchronization of the process of mediator release; substances blocking beta-adrenoceptors (atenolol, propranolol) blocked this effect. Clonidine and phenylephrine, which activate alpha-receptors, had no effect on the kinetics of secretion, while the alpha-blocker phentolamine had no effect on the synchronizing action of noradrenaline. Reconstruction of multiquantum EPC from changes in the level of synchronization in the release of individual quanta, showed that EPC amplitude increased in response to noradrenaline by 17%, and that this was due only to alterations in the time course of secretion. These data led to the conclusion that there is a special presynaptic mechanism which facilitates the action of sympathomimetics, acting via beta-adrenoceptors.
In recent years, considerable attention has been focused on the pressor effects of nonprescription sympathomimetic agents. The impact and usage of these agents especially ephedrine, pseudoephedrine, phenylpropanolamine and phenylephrine, in hypertensive patients has been the topic of constant debates. The present review is an attempt to report and evaluate all the clinical trials and cases of pressor reactions associated with these 4 agents. The study protocols used in these clinical trials are examined and comments made on any diversion from the standard design. Many factors are found to cause the discrepancies in the data available. It is concluded that ephedrine and phenylpropanolamine are best avoided by hypertensive patients due to higher probability of causing pressor reactions. Data on pseudoephedrine and phenylephrine appear to indicate non-significant effects on blood pressure of normotensive subjects when used at the recommended oral dose as nasal decongestants. Phenylephrine is also commonly employed in nasal and eye drops and the limited data available appear to support its usage in hypertensive patients. However, it is noted that most of the clinical trials involve normotensive subjects and the majority of the results could not be verified due to inadequacies in the study design. This paucity and inconclusive information on hypertensive patients warrants further investigations with emphasis on the study protocols used.
The beta-blocker (-)-pindolol produces intrinsic sympathomimetic activity manifested clinically by cardiostimulation, but the beta-adrenoceptor subtype, which mediates these effects, is unknown. Recent work indicates the existence of a (-)-propranolol-resistant site of the cardiac beta(1)-adrenoceptor and we propose that it mediates the cardiostimulation evoked by (-)-pindolol. We compared the interaction of (-)-pindolol both with human atrial myocardium and with recombinant beta(1)-adrenoceptors. The effects of (-)-pindolol on paced human atrial trabeculae were studied in the presence of 3-isobutyl-1-methylxanthine (IBMX; 20 microM). (-)-Pindolol caused small negative and positive inotropic effects at nanomolar and micromolar concentrations respectively, which were unaffected by N(G)-monomethyl-L-arginine (L-NMMA, 10 microM), inconsistent with an involvement of nitric oxide. (-)-Pindolol, in the presence of (-)-propranolol, increased atrial contractile force and cAMP through recombinant beta(1)-adrenoceptors with identical potency (-logEC(50)M=6.5). The positive inotropic effects of (-)-pindolol were resistant to blockade by L-748,337 (100 nM), a beta(3)-adrenoceptor antagonist. (-)-CGP12177, known to act through the (-)-propranolol-resistant site of the beta(1)-adrenoceptor, also increased with similar potency atrial contractile force (-logEC(50)M=7.6) and cAMP at recombinant beta(1)-adrenoceptors (-logEC(50)M=7.7). (-)-Pindolol blocked the effects of (-)-CGP12177 in human atrium and recombinant beta(1)-adrenoceptors with similar equilibrium dissociation constants (pK(B)=6.5 and 6.3). Thus, stimulant potency and blocking potency of (-)-pindolol against (-)-CGP12177 agree. In contrast, (-)-pindolol was 200-400 times more effective at blocking the effects of a catecholamine than the effects of (-)-CGP12177 in both human atrium (pK(B)=9.1) and at recombinant beta(1)-adrenoceptors (pK(B)=8.6). We conclude that the cardiostimulant effects of (-)-pindolol in human atrial myocardium are mediated through a (-)-propranolol-resistant site of the beta(1)-adrenoceptor with low affinity for (-)-pindolol. In contrast, (-)-pindolol blocks the effects of catecholamines through a high-affinity site of the beta(1)-adrenoceptor. beta(3)-Adrenoceptors are not involved in the atrial effects of (-)-pindolol.
The intrinsic sympathomimetic activity (ISA) of a beta-adrenoceptor blocker can be mediated by beta(1)- or beta(2)-adrenoceptors. The aim of this study was to characterize the ISA of the beta-adrenoceptor blocker carteolol in healthy volunteers. Two approaches were employed. First, we assessed the effects of carteolol (20, 40 or 80 mg p.o.) on blood pressure, heart rate and heart-rate corrected duration of electromechanical systole (QS(2)c, a measure of cardiac contractility) in the volunteers. Carteolol dose-dependently increased systolic blood pressure, heart rate and contractility and decreased diastolic blood pressure. The beta(1)-adrenoceptor blocker bisoprolol did not attenuate these carteolol effects, but rather enhanced the effects on heart rate and systolic blood pressure. Second, we treated volunteers for 7 days with 1 x 20 mg/day carteolol and assessed lymphocyte beta(2)-adrenoceptor density (by (-)-[(125)I]-iodocyanopindolol binding) and functional responsiveness (by 10 muM isoprenaline-induced increase in lymphocyte cyclic AMP content). Carteolol significantly reduced lymphocyte beta(2)-adrenoceptor density and function. After withdrawal of carteolol lymphocyte beta(2)-adrenoceptor density and function recovered only very slowly and had not returned to control levels 11 days after carteolol withdrawal. In conclusion, the fact that, on the one hand, the cardiovascular effects of carteolol were not attenuated by the beta(1)-adrenoceptor blocker bisoprolol and, on the other, carteolol significantly decreased lymphocyte beta(2)-adrenoceptor density and function is in favour of the idea that the ISA of carteolol is mediated by beta(2)-adrenoceptors. Involvement of an additional receptor site (e.g. the propranolol-resistant state of the beta(1)-adrenoceptor), however, cannot be excluded.
Although all beta blockers have been found to be effective in the symptomatic relief of angina pectoris, the importance of intrinsic sympathomimetic activity (ISA) has not been studied extensively. In a randomized, double-blind study, we administered equipotent doses of propranolol (10, 20, and 40 mg four times a day) and pindolol (2.5, 5, and 10 mg four times a day), a beta blocker with significant ISA, to 52 patients with angina. Both agents were found to be effective in the treatment of angina. At peak dose, propranolol reduced the number of angina attacks per 2 weeks from 29.29 +/- 4.79 to 18.0 +/- 4.4 (p = 0.021) (a 39% reduction) and increased the exercise tolerance on the treadmill from 7.55 +/- 0.67 METS to 9.36 +/- 0.58 (p = 0.002). Pindolol decreased the number of anginal attacks per 2 weeks from 16.48 +/- 2.63 to 8.65 +/- 2.46 (p = 0.0027) (a 48% reduction) and increased exercise tolerance from 7.95 +/- 0.56 METS to 9.40 +/- 0.57 (p = 0.0245). At the end of the maximum tolerated exercise, propranolol decreased the heart rate from 110.00 +/- 3.41 to 99.71 +/- 3.74 (p = 0.0015). Pindolol also decreased the heart rate at the maximum tolerated exercise from 113.59 +/- 3.24 to 108.12 +/- 3.16 (p = 0.0102). At rest, however, propranolol induced a more pronounced (p = 0.0066) decrease in heart rate (from 69.00 +/- 1.85 to 61.50 +/- 1.99; p = 0.0018), whereas pindolol did not significantly affect the resting heart rate (65.37 +/- 1.47 to 65.5 +/- 1.44; p = 0.9392). In addition propranolol decreased echocardiographically determined ejection fraction from 0.57 +/- 0.02 to 0.15 +/- 0.01 (p = 0.04) and increased the left ventricular end-diastolic volume from 71.8 +/- 3.2 to 92.2 +/- 1.9 ml (p = 0.003), whereas pindolol did not affect the ejection fraction and caused a less pronounced (p = 0.03) increase in end-diastolic volume (from 70.8 +/- 1.8 to 80.2 +/- 2.8; p = 0.02). The data indicate that both propranolol and pindolol are effective in the treatment of angina pectoris and that pindolol decreases the resting heart rate and ejection fraction and increases the left ventricular end-diastolic volume to a lesser extent than propranolol.
The therapeutic importance of the ancillary pharmacologic property of partial agonist activity, or intrinsic sympathomimetic activity (ISA), of a beta-adrenoceptor antagonist is controversial. Its pharmacologic definition and accepted physiologic potential are now joined by convincing evidence that ISA may have important therapeutic implications. The ability to support basal cardiac functions while preventing the potential hazards of random sympathetic stimulation is an important attribute of this property, particularly in the damaged heart. The beneficial effects of ISA on peripheral blood flow, systemic vascular resistance and left ventricular afterload are established. Although all beta-blocking drugs are contraindicated in patients with asthma, ISA appears to be at least as important as cardioselectivity in offsetting some of the increase in airway resistance that results from beta blockade alone both at rest and during exertion. These pharmacodynamic consequences of ISA may explain the lesser reduction in exercise tolerance afforded by beta-blocking drugs with ISA than by those without. ISA may also enhance the primary oxygen-sparing effects of beta blockade in the ischemic myocardium by reducing coronary resistance, enhancing coronary blood flow, and reducing anaerobic metabolism. The adverse effects of beta-blocking drugs on blood lipids and carbohydrate metabolism also appear to be largely negated in drugs with ISA. The risks of rebound effects from abrupt withdrawal are significantly less in drugs with ISA than in those without.
The possession of intrinsic sympathomimetic activity (ISA) by a beta-adrenoceptor blocking drug results in a number of different pharmacologic properties. Most profound are the central hemodynamic effects. A drug with a significant degree of ISA results in less of a decrease in heart rate at rest and cardiac output, and, at least partly because of this, less of a decrease in peripheral blood flow. If prevailing sympathetic tone is low enough (e.g., during sleep) and the degree of ISA is sufficient, an increase in heart rate may be seen from an ISA-possessing drug. If the drug possesses beta 2 ISA, then a peripheral vasodilation action from stimulation of beta 2 vasodilator receptors may also be relevant. If high levels of exercise and full dosages of the drugs are used, a beta-blocking drug with ISA produces less of a decrease in heart rate. In asthmatic subjects, the modest beta-stimulant action on bronchial smooth muscle is not important, as these patients are potentially sensitive to any receptor blockade. Isoprenaline responses are inhibited to a similar degree compared with inhibition of exercise tachycardia, by nonselective drugs with and without ISA, whereas beta 1 selective agents produce much less inhibition of isoprenaline-induced tachycardia. A drug with ISA "down regulates" beta receptors; thus, when the drug is withdrawn there is no post-beta-blocking drug hypersensitivity in contrast to agents without ISA. There is evidence that ISA results in less of a disturbance in certain metabolic processes, particularly lipid metabolism and the metabolism of liver-metabolized drugs.